Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ^−/− (NSG) mice by ex vivo modulation of human CD4⁺ T cells

Abstract

NOD.Cg-Prkdcscid IL-2rg tm1Wjl /SzJ (NSG) mice are a valuable tool for studying Graftversus-Host-Disease (GvHD) induced by human immune cells. We used a model of acute GvHD by transfer of human peripheral blood mononuclear cells (PBMCs) into NSG mice. The severity of GvHD was reflected by weight loss and was associated with engraftment of human cells and the expansion of leukocytes, particularly granulocytes and monocytes. Pre-treatment of PBMCs with the anti-human CD4 antibody MAX.16H5 IgG1 or IgG4 attenuated GvHD. The transplantation of 2 3 10 7 PBMCs without anti-human CD4 pre-treatment induced a severe GvHD (0% survival). In animals receiving 2 3 10 7 PBMCs pre-incubated with MAX.16H5 IgG1 or IgG4, GvHD development was reduced and survival was increased. Immune reconstitution was measured by flow cytometry and confirmed for human leukocytes (CD45), CD3 /CD41 T helper cells. Human B cells (CD19) and monocytes (CD14) could not be detected. Histopathological analysis (TUNEL assay) of the gut of recipient animals showed significantly less apoptotic crypt cells in animals receiving a MAX.16H5 IgG1 pre-incubated graft. These findings indicate that preincubation of an allogeneic graft with an anti-human CD4 antibody may decrease the frequency and severity of GvHD after hematopoietic stem cell transplantation (HSCT) and the need of conventional immunosuppressive drugs. Moreover, this approach most probably provides a safer HSCT that must be confirmed in appropriate clinical trials in the future. V C 2016 International Society for Advancement of Cytometry

Exploring Crimean-Congo Hemorrhagic Fever Virus-Induced Hepatic Injury Using Antibody-Mediated Type I Interferon Blockade in Mice

“…4D). Baseline liver enzyme levels in NSG mice were similar to those in BL6 mice (35). The levels of ALT in all infected mice were significantly increased over those in control animals (one-way ANOVA, P Ͻ 0.05).…”

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

“…Humanized mice have been widely used to model human immune cell function in vivo (1)(2)(3)(4)(5)(6). In the Hu-PBL-SCID model, a major limitation of studying human T-cell function is the rapid development of fatal xenogeneic GVHD that not only shortens the experimental time window but also confounds the analysis of human T cell function due to the underlying ongoing acute GVHD that eventually kills the mice (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In the present study, we have overcome this limitation by eliminating expression of murine MHC class I and II in NSG mice.…”

“…The Hu-PBL-SCID model has been used to study human infectious agents, tissue transplantation, and human T-cell immune function (2,(12)(13)(14). One of the primary uses of this model is the study of acute graft-versus-host disease (GVHD) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), a major problem in clinical hematopoietic stem cell transplantation (26). NSG mice engrafted with human PBMCs develop an acute xenogeneic GVHD-like disease upon recognition of the murine cells and tissues by mature human T cells (23).…”

The expanded cytometry concept

“…In many cases, the sheer numbers of RBCs in leukocyte preparations are a problem but in blood products for infusion it's the leucocytes and leucoreduction. Thus, for clinical applications it is essential to minimize their potentially adverse effects like graft versus host disease in the transfused patient. To evaluate tests quantifying blood products for residual leucocytes Zeng and colleagues conducted a multicentric study with commercial tests and found good agreement between laboratories as you can find in detail in their study report (this issue, page 420).…”